Immunotherapy with rituximab, an unlabeled monoclonal antibody (MoAb) to CD20, has made a major impact on the treatment of non- Hodgkin lymphoma (NHL); however, most responses are partial and complete remissions (CR) remain elusive. Y2B8 is an anti-CD20 radioimmunoconjugate consisting of a murine MoAb ibritumomab bound to Y-90, a high energy, beta-emitting radioisotope that can be routinely administered as an outpatient. Radioimmunotherapy (RIT) with Y2B8 has produced a higher overall response rate (80%) and a higher CR rate (30%) than unlabeled rituximab with excellent patient tolerance. In addition to targeting the tumor cell with unlabeled and radiolabeled antibody, it is our hypothesis that the patient's blood and intratumoral immune effector cells (NK, T-cells, dendritic cells) also should be targeted to improve tumor response and survival. A new class of immunostimulatory agents consisting of oligodeoxynucleotides (ODN) containing the cytosine-guanine (CpG) motif have been shown to up- regulate CD20 expression on malignant B-cells and stimulate blood immune effector cells (IECs) to produce cytokines and a Th1 immune response. A phase I trial of CpG ODN in patients with B-cell NHL has demonstrated that CpG ODN can be safely administered in repeated doses to NHL patients with myelosuppression. Project IV will test the effects on CpG on the tumor and patient IECs in the context of RIT with U2B8 through 4 Specific Aims. Aim 1 will conduct a phase I trial that will add 3 doses of synthetic CpG ODN 7909 to rituximab and Y2B8 in order to develop a new treatment approach for patients with relapsed NHL. Aim 2 will utilize 111-Indium ibritumomab imaging pre- and post- CpG to test the hypothesis that CpG can indeed up-regulate CD20 on tumor and enhance Y2B8 tumor: normal organ biodistribution. Aim 3 will perform translational research studies on blood and tumor samples to learn whether CpG, the critical genetic and biologic responses to CpG in malignant B cells and benign IECs in indolent and aggressive clinicopathologic types of NHL using fresh tumor samples and gene expression microarrays. In summary, Project IV will develop through a Phase I trial a new treatment regimen combining CpG with MoAb and RIT. The effects of CpG on malignant lymphoma cells and IECs will be investigated by gene expression arrays and specialized immunoassays on samples from patients participating in the trial to learn how to better exploit the immune system for lymphoma therapy.